1. Field of the Invention
The present invention relates generally to the field of cancer including tumor therapy. More particularly, the present invention relates to the treatment of solid cancers, including solid tumors, and the prevention or reduction of cancer metastasis, by chemoablation of cancer cells by an agent which also stimulates the generation of cancer-specific T-cells, a process referred to herein as immunostimulatory chemoablation. The present invention further contemplates combination therapy comprising immunostimulatory chemoablation and one or more other therapeutic regimens, which enhance, co-operate and/or synergize with the cancer-specific T-cells induced by the chemoablation. The present invention also relates to pharmaceutical compositions for use in treating cancers.
2. Description of the Prior Art
Bibliographic details of references provided in the subject specification are listed at the end of the specification.
Reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in any country.
Although chemotherapy has been useful to prolong survival, to increase tissue conserving surgery, and to increase remission rates for several cancer types, the high mortality of cancers such as breast, lung and colorectal carcinomas, which account for the majority of cancer deaths, have remained problematic during the past 25 years from the standpoint of achieving significant advances in outcomes. This is true despite major changes in surgical and radiation protocols including combinatorial drug and drug-radiation regimens and new approaches to the staging of treatments. This relatively modest improvement is reflected in National Cancer Institute data as presented in the Surveillance, Epidemiology and End Results (SEER) 1973-1997 Cancer Statistics Review (NCI-NIH 2000).
From these data, it appears that there has been little change in the ratio of incidence (diagnosis) to mortality rate in the short term period 1997-2000 for breast cancer (180200 diagnosed/41945 deaths in 1997 vs 182800/40800 in 2000), for lung cancer (178100/153200 in 1997 vs 164100/156900 in 2000) and for colorectal cancer (131200/56695 in 1997 vs 130200/56300 in 2000). Some changes do seem to be attributable to various evolving “conventional” treatments over the long term when one compares 1950 with 1997 data. However, there have been so many therapeutic, diagnostic and demographic changes during this extended time period that it is extremely difficult to clearly attribute improvements in outcomes to specific “standard of care” regimens. For example, based on the SEER report, the ratio of the annual % change for diagnosis to the annual % change of the mortality rate during the period 1950-1997 is: breast (+1.3%/0.1%), lung (+2.3%/+2.9%) and colorectal (0.1%/0.9%). Using estimates for the past 20 years, increasing diagnosis for breast (+29%) and lung (+58%) has been observed but only a 2% decline in breast cancer mortality and a disturbing 77% increase in lung cancer mortality during this time. Even with the remarkable advances in health care during the past 50 years there appear to be only modest and interpretatively complicated changes for outcomes in the treatment of high mortality cancers; except for lung cancer where the diagnosis and especially the mortality have been clearly on the rise.
In work leading to the present invention, the subject inventors recognized that one limitation of current chemotherapeutic agents is its toxicity to the immune system. Thus, combining chemotherapy with immune-based therapies, which intend to induce anti-cancer T-cell activity, is often compromised by the immunosuppressive effect of the chemotherapy, which generally suppress formation of cancer-specific T-cells. Although some local chemotherapy can induce anti-cancer immunity, it is widely recognized that chemotherapeutic treatments result in suboptimal induction of functional anti-cancer T-cells.
Accordingly, there is a clear need for more effective therapeutic treatments for solid cancers which include solid tumors. The present invention provides a method of treating a range of solid cancers in a subject using, inter alia, an agent which may be applied directly or proximally to the cancer and which operates via a mode of action which induces immunostimulatory chemoablation of the cancer cells. In particular, the chemoablation agent stimulates the generation of T-cells and more particularly CD8+ T-cells and CD4+ T-cells having cancer cell specificity and further that this immunostimulatory chemoablatory can enhance, co-operate and/or synergize with other immune-based therapeutic regimens to enhance anti-cancer therapy.